A Global Cndp1-Knock-Out Selectively Increases Renal Carnosine and Anserine Concentrations in an Age- and Gender-Specific Manner in Mice

• Main Authors: Tim Weigand, Florian Colbatzky, Tilman Pfeffer, Sven F. Garbade, Kristina Klingbeil, Michael Becker, Johanna Zemva, Ruben Bulkescher, Robin Schürfeld, Christian Thiel, Nadine Volk, David Reuss, Georg F. Hoffmann, Marc Freichel, Markus Hecker, Tanja Poth, Thomas Fleming, Gernot Poschet, Claus P. Schmitt, Verena Peters
• Format: Article
• Language: English
• Published: MDPI AG 2020-07-01
• Series: International Journal of Molecular Sciences
• Subjects: carnosinase 1; CN1; <i>Cndp1</i>; carnosine; anserine; kidney
• Online Access: https://www.mdpi.com/1422-0067/21/14/4887
• ISSN: 1661-6596; 1422-0067

Carnosinase 1 (CN1) is encoded by the <i>Cndp1</i> gene and degrades carnosine and anserine, two natural histidine-containing dipeptides. In vitro and in vivo studies suggest carnosine- and anserine-mediated protection against long-term sequelae of reactive metabolites accumulating, e.g., in diabetes mellitus. We have characterized the metabolic impact of CN1 in 11- and 55-week-old <i>Cndp1</i>-knockout (<i>Cndp1</i>-KO) mice and litter-matched wildtypes (WT). In C<i>ndp1</i>-KO mice, renal carnosine and anserine concentrations were gender-specifically increased 2- to 9-fold, respectively in the kidney and both most abundant in the renal cortex, but remained unchanged in all other organs and in serum. Renal oxidized/reduced glutathione concentrations, renal morphology and function were unaltered. In <i>Cndp1</i>-KO mice at week 11, renal asparagine, serine and glutamine levels and at week 55, renal arginine concentration were reduced. Renal heat-shock-protein 70 (<i>Hspa1a/b</i>) mRNA declined with age in WT but not in <i>Cndp1</i>-KO mice, transcription factor heat-shock-factor 1 was higher in 55-week-old KO mice. Fasting blood glucose concentrations decreased with age in WT mice, but were unchanged in <i>Cndp1-KO</i> mice. Blood glucose response to intraperitoneal insulin was gender- but not genotype-dependent, the response to intraperitoneal glucose injection was similar in all groups. A global <i>Cndp1-</i>KO selectively, age- and gender-specifically, increases renal carnosine and anserine concentrations, alters renal amino acid- and HSP70 profile and modifies systemic glucose homeostasis. Increase of the natural occurring carnosine and anserine levels in the kidney by modulation of CN1 represents a promising therapeutic approach to mitigate or prevent chronic kidney diseases such as diabetic nephropathy.